Succinylcholine prefilled syringe, compositions and methods

ABSTRACT

Pre-filled syringes, pharmaceutical compositions, and kits and methods relating to same allow for emergency administration of one or more drugs from prefilled glass syringes to a patient via a needleless connector. In preferred embodiments, the prefilled glass syringe has a drug volume of at least 5 mL, has a Luer-lock, and has a syringe tip with an internal channel that has a diameter of about 1.7 mm. Such syringes advantageously allow storage of emergency drugs without leaching of plastic materials and degradation, and substantially improve the safety profile where the syringe is attached to an IV line via a needleless connector.

This application claims priority to allowed US patent application withthe Ser. No. 16/272,815, which was filed Feb. 11, 2019, which claimspriority to US provisional patent application with the Ser. No.62/642,326, which was filed Mar. 13, 2018, the contents of which areherein incorporated by reference.

FIELD OF THE INVENTION

The present disclosure relates to kits, prefilled syringes,pharmaceutical compositions and methods of use thereof, particularly asit relates to prefilled glass syringes containing emergency medicationfor administration through needleless connectors.

BACKGROUND OF THE INVENTION

The background description includes information that may be useful inunderstanding the present disclosure. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

All publications and patent applications herein are incorporated byreference to the same extent as if each individual publication or patentapplication were specifically and individually indicated to beincorporated by reference. Where a definition or use of a term in anincorporated reference is inconsistent or contrary to the definition ofthat term provided herein, the definition of that term provided hereinapplies and the definition of that term in the reference does not apply.

Needleless devices for connecting intravenous (IV) catheters,administration sets, and syringes have been developed over the lastdecades and helped significantly reduce needlestick injuries amonghealth care providers. Unfortunately, the use of needleless connectorshas also been associated with an increase in various complications suchas catheter-related bloodstream infection and catheter lumen occlusion.To circumvent at least some of these problems, various improvements havebeen implemented. For example, several simple needleless connectors usea split septum and/or other non-moving parts to avoid backflow of bloodinto the IV line while still allowing needleless access to the IV line.More complex needleless connectors employ internal moving componentssuch as unidirectional valves to control the flow of fluids within theconnector. While simple connectors advantageously provide simplicity ofuse and manufacture, negative fluid displacement or reflux will oftenoccur upon withdrawal of the cannula due to their relatively large size.On the other hand, connectors with mechanical valves are more complexand therefore less simple in manufacture, but typically have no or onlyminor reflux.

A representative complex needleless connector is shown in Prior Art FIG.1, in which a syringe with a male luer tip 110 is coupled to aneedleless connector with a reversed internal blunt cannula 120.Exemplary complex needleless connectors are described, for example, inU.S. Pat. Nos. 9,205,243 and 9,750,926, and such and similar connectorsmay further include a sealing member and regulator acting as a secondvalve as is described, for example, in US Publication Nos. 20180099137and 20190001114. While such and other complex needleless connectorseliminate the risk of needlestick injuries and at least conceptuallysimplify operation, catheter related blood stream infections have becomemore prevalent.

Worse yet, and particularly in emergency settings where certain drugs(e.g., adenosine, amiodarone, succinylcholine, etc.) need to beadministered without delay and interruption, complex needlelessconnectors can contribute to catastrophic failure. In a Drug SafetyCommunication, the FDA had more recently indicated that pre-filled glasssyringes can become clogged and malfunction during the process ofconnecting them to pin-activated needleless IV access systems (see PriorArt FIGS. 2A and 2B). Unfortunately, such failure is not detected untilafter the syringe is inserted into the pin-activated needleless i.v.access system. For example, the action of inserting the syringe cancause the pin in the access system to clog or break off in the syringetip, thus preventing delivery of the medication and necessitatingplacement of a new i. v. access line. As a consequence, the FDA advisedthat the use of needleless pre-filled glass syringes in emergencysituations should be avoided, if possible (see URL:www.fda.gov/Drugs/DrugSafety/ucm254215.htm). Moreover, because of recentadverse glass syringe connection events, the FDA has recognized thatdemonstrating conformity to the ISO 11040-4 standard alone does notensure that the glass syringes can be properly connected to connectingdevices. Therefore, sponsors who seek to rely on conformity to the ISO11040-4 standard in submissions for glass syringe products should alsosubmit information from supplemental tests to demonstrate that the glasssyringe can be properly connected to connecting devices. Such safeconnection has been elusive and challenging, particularly for prefilledglass syringes.

Thus, even though various methods of delivering emergency medicationfrom syringes via needleless connectors are known in the art, all oralmost all of them suffer from various disadvantages. Consequently,there is a need to provide improved devices, kits, and methods usingglass syringes that improve safety and reliability of drugadministration in emergency settings.

SUMMARY OF THE INVENTION

Various devices, compositions, kits, and methods are presented in whichproblems associated with emergency IV administration of various drugcompositions via needleless connectors can be avoided. In especiallypreferred aspects, the emergency drug composition comprisessuccinylcholine that is contained in a prefilled glass syringe, and thesyringe has a Luer-lock and a syringe tip with an internal channel thathas a diameter of about 1.7 mm.

In one aspect of the inventive subject matter, the inventors contemplatea method for intravenously administering succinylcholine to a patientand/or providing skeletal muscle relaxation to a patient in need thereofthat includes the steps of (a) providing a prefilled glass syringecontaining a succinylcholine composition, wherein the succinylcholinecomposition comprises succinylcholine chloride, sodium chloride, andwater, wherein the succinylcholine composition is substantially free ofpreservatives, and wherein the succinylcholine composition has a pH ofabout 3.0 to about 4.5, and wherein the syringe has a Luer-lock and asyringe tip with an internal channel that has a diameter of about 1.7mm; (b) reversibly attaching the syringe to a patient's intravenous linevia the Luer-lock; (c) delivering the succinylcholine composition fromthe syringe into the patient's intravenous line; and (d) administeringthe succinylcholine composition from the patient's intravenous line tothe patient.

In some embodiments, the step of reversibly attaching the syringe to apatient's intravenous line comprises attaching the syringe to aneedleless connector, which may include a reversed internal bluntcannula. Most typically, but not necessarily, the glass syringe has avolume of at least 5 mL.

In other embodiments, the succinylcholine composition has an osmolalityof about 260 to about 340 mOsm/kg, and/or the succinylcholine chlorideis present in the succinylcholine composition in an amount of about 20mg/mL and the sodium chloride is present in the succinylcholinecomposition in an amount of about 6 mg/mL. It is further contemplatedthat the succinylcholine composition further comprises a pH adjustingagent (e.g., hydrochloric acid and/or sodium hydroxide), and/or that thepH of the succinylcholine composition is about 3.6.

With respect to the syringe it is contemplated that the syringe has aglide force of about 1 to about 20 N, and/or that the syringe has abreak loose force of about 10 to about 30 N. In further embodiments, thesyringe contains about 5 mL or about 10 mL of the succinylcholinecomposition, which may be administered to the patient at a rate of about0.5 to about 10 mg per minute. Preferably, the succinylcholinecomposition in the glass syringe contains not more than about 6% totalimpurities after storage at 2-8° C. for 15 months as determined by HPLC.Viewed from a different perspective, the succinylcholine compositiondisposed in the glass syringe contains not more than about 4%succinylmonocholine chloride after storage at 2-8° C. for 15 months asdetermined by HPLC, and/or the succinylcholine composition disposed inthe glass syringe contains not more than about 1% succinic acid afterstorage at 2-8° C. for 15 months as determined by HPLC.

In another aspect of the inventive subject matter, the inventorscontemplate a kit that comprises a prefilled glass syringe containing asuccinylcholine composition, wherein the succinylcholine compositioncomprises succinylcholine chloride, sodium chloride, and water, whereinthe succinylcholine composition is substantially free of preservatives,and wherein the succinylcholine composition has a pH of about 3.0 toabout 4.5. Preferably, the syringe has a Luer-lock and a syringe tipwith an internal channel that has a diameter of about 1.7 mm.

Most typically, the glass syringe has a volume of at least 5 ml.Contemplated kits may further include an IV administration set with atleast one needleless connector (e.g., needleless connector with areversed internal blunt cannula).

With respect to contemplated succinylcholine compositions it istypically preferred that the succinylcholine composition has anosmolality of about 260 to about 340 mOsm/kg, and/or that thesuccinylcholine chloride is present in the succinylcholine compositionin an amount of about 20 mg/mL and the sodium chloride is present in thesuccinylcholine composition in an amount of about 6 mg/mL. Moreover itis contemplated that the succinylcholine composition further comprises apH adjusting agent (e.g., hydrochloric acid and/or sodium hydroxide) andthat the pH of the succinylcholine composition is about 3.6. In someembodiments, the succinylcholine composition disposed in the glasssyringe contains not more than about 6% total impurities after storageat 2-8° C. for 15 months as determined by HPLC, and in other embodimentsthe succinylcholine composition disposed in the glass syringe containsnot more than about 4% succinylmonocholine chloride after storage at2-8° C. for 15 months as determined by HPLC. In further embodiments, thesuccinylcholine composition disposed in the glass syringe contains notmore than about 1% succinic acid after storage at 2-8° C. for 15 monthsas determined by HPLC.

Therefore, viewed from a different perspective, the inventors alsocontemplate a kit that comprises a prefilled glass syringe containing adrug for emergency medical administration, wherein the glass syringe hasa volume of at least 5 ml, wherein the glass syringe has a luer-lock anda syringe tip with an internal channel that has a diameter of about 1.7mm, and wherein the glass syringe and the drug are sterilized.

In particularly preferred aspects, the drug is succinylcholine,ephedrine, amiodarone, adenosine, epinephrine, atropine,methylprednisolone, metoprolol, diltiazem, or procainamide, andcontemplated kits may further include an IV administration set with atleast one needleless connector, and particularly a needleless connectorwith a reversed internal blunt cannula.

Viewed from yet another perspective, the inventors contemplate aprefilled glass syringe containing a drug composition for emergencymedical administration of the drug through a needleless connector,wherein the glass syringe has a volume of at least 5 ml, wherein theglass syringe has a luer-lock, and wherein the glass syringe has asyringe tip with an internal channel that has a diameter of about 1.7mm.

For example, suitable drug compositions include succinylcholine,ephedrine, amiodarone, adenosine, epinephrine, atropine,methylprednisolone, metoprolol, diltiazem, and procainamide. Forexample, the drug composition may comprise succinylcholine chloride,sodium chloride, and water, wherein the succinylcholine composition issubstantially free of preservatives, and wherein the succinylcholinecomposition has a pH of about 3.0 to about 4.5.

Various objects, features, aspects, and advantages will become moreapparent from the following detailed description of preferredembodiments, along with the accompanying drawing in which like numeralsrepresent like components.

BRIEF DESCRIPTION OF THE DRAWING

Prior Art FIG. 1 depicts a cross sectional view of an exemplary knownneedleless connector with a reversed internal blunt cannula attached toa syringe with a male luer tip.

Prior Art FIG. 2A depicts a damaged/clogged syringe tip afterdisconnection from a needleless connector with a reversed internal bluntcannula, and Prior Art FIG. 2B depicts a glass syringe tip and brokenoff tip of a reversed internal blunt cannula of a needleless connector.

FIG. 3 depicts a comparison between a conventional attachment of a glasssyringe to a needleless connector (left) and an attachment of a widemouth glass syringe to a needleless connector (right) according to theinventive subject matter.

FIG. 4 depicts an exemplary connection between a syringe according tothe inventive subject matter to a needleless connector with a reversedinternal blunt cannula.

FIGS. 5A and 5B depict exemplary labels for prefilled syringes.

DETAILED DESCRIPTION

The inventors have now discovered that various emergency medications canbe rapidly and safely administered through a needleless connector (thatis typically fluidly coupled to an IV line into a patient) without theattendant risk of clogging or breakage that has been encountered in thepast. More particularly, the inventors discovered that the likelihood ofbreakage can be significantly reduced by using a syringe having awidened inner diameter of a syringe tip. Advantageously, the inventorsobserved that such a widened inner diameter substantially increased thetolerance of the tip to angled insertion into a needleless connector andso dramatically decreased the likelihood of damaging static or movinginternals of the needleless connector. Moreover, the inventors observedthat such widening did not cause significant mechanical weakening of thesyringe tip that could otherwise lead to chipping or breaking of the tipwhere a glass syringe is used.

For example, FIG. 3 exemplarily depicts on the left hand a conventionalsyringe 300 that has a syringe tip 310 having an internal diameter 320(here: 1.1 mm). The syringe also includes a luer lock connector 330 thatis releasably coupled to matching luer lock of a needleless connector340 (internals not shown) of an IV line. In contrast, on the right handsyringe 301 is shown having a syringe tip 311 with a significantlylarger internal diameter 321 (here: 1.7 mm). The syringe also includes aluer lock connector 331 that is releasably coupled to matching luer lockof a needleless connector 341 (internals not shown) of an IV line. Asshould be readily apparent, the wider internal diameter accommodatesangled insertion of the syringe tip 311 without jamming or breaking theinternals (such as a reversed internal blunt cannula). FIG. 4schematically illustrates one such embodiment in which syringe 401 has asyringe tip 411 with a significantly larger internal diameter. As can beseen, the reversed internal blunt cannula 442 of needleless connector441 does not contact the internal walls of syringe tip 411. Instead, dueto the wider inner diameter of the tip, an annular void space betweenthe outer surface of the reversed internal blunt cannula and theinternal walls of syringe tip is present that reduces or even entirelyeliminates the risk of breakage or jamming of the front end of thereversed internal blunt cannula. FIGS. 5A and 5B depict exemplary labelsfor prefilled syringes according to the inventive subject matter.

Notably, despite the loss of a sealing surface (i.e., the outsidesurface of reversed internal blunt cannula against internal wall of thesyringe tip) the connection between the syringe and the needlelessconnector nevertheless remained fluidly sealed by compression of elasticmember 444 against the front end of the syringe tip and further bysealing engagement between the outer surface of the syringe tip 411 andthe inner surface of the front portion of the connector that receivesthe syringe tip 411. Even at elevated pressure, these remaining surfacesmaintained a fluid-tight contact that allowed rapid delivery of fluidsthrough the connection.

Most preferably, the syringe for use in conjunction with the teachingsherein may be a glass syringe (e.g., borosilicate glass), and in lesspreferred embodiments also a syringe manufactured from a polymericmaterial such as polypropylene or polyethylene. Moreover, it ispreferred that the syringe has a volume of at least 5 mL or at least 10mL, however, smaller volumes are also expressly contemplated. In oneembodiment, the syringe has a volume of 5 mL. In another embodiment, thesyringe has a volume of 10 mL. With respect to the tip it typicallypreferred that the tip is a centrally located tip, but eccentric tipsare also deemed suitable. Most typically, the syringe tip will have anouter diameter, angle, and length that accommodate standard hubdimensions of luer lock needles and other luer lock equipment. Standardsfor luer lock connections are described in ISO 80369 and in DIN and ENstandard 1707:1996 and 20594-1:1993, incorporated by reference herein.

For example, a typical tip of a syringe for luer-type connection willhave a cone shaped configuration acting as the male portion of the luerlock with an overall length of about 7.5 mm from proximal to distal end(with respect to the barrel) of the tip, the proximal end of the tiphaving an outer diameter of about 4.45 mm and the distal end of the tiphaving an outer diameter of about 4.00 mm. Thus, a taper angle (relativeto a hypothetical axis running through the center of the barrel and tip)of the tip walls between 0.5 degree and 5.0 degree are generally deemedsuitable. However, the actual taper angle will in most cases correspondto the female luer lock counterpart such that the outer surface of themale and inner surface of the female connector will sealingly coupledthe male and female portions (i.e., have the same angle along at least70% of the length of the male tip).

With respect to the overall length of the tip as measured from proximalto distal end it is generally preferred that the length will be betweenabout 8.5 mm to about 6.0 mm, however, various longer and shorterlengths are also deemed suitable for use herein. For example, suitablelengths include those between 5.5 mm and 7.0 mm, and between 6.0 mm and8.0 mm, and between 7.0 mm and 9.0 mm. However, lengths of equal or lessthan 8.0 mm are generally preferred. With respect to the inner diameterof the tip it is generally preferred that the inner diameter is constantfrom the proximal to the distal end of the tip. Most typically the innerdiameter will be about 1.7 mm, however various other inner diameters arealso deemed suitable for use herein. For example, alternative innerdiameters will generally be greater than 1.1 mm, or greater than 1.3 mm,or greater than 1.5 mm, or greater than 1.7 mm, or greater than 1.9 mm,or even greater. Thus, suitable inner diameters will be between 1.2-2.2mm, or between 1.4-2.0 mm, or between 1.6-1.8 mm, or between 1.3-1.6 mm,or between 1.5-1.9 mm, or between 1.6-2.0 mm. Viewed from a differentperspective, the inner diameter and/or the length of the tip will beselected such that the syringe and tip can be inserted into theneedleless connector at an angle (with respect to a hypothetical centralaxis extending through the barrel and the tip of the syringe and ahypothetical central axis longitudinally extending through theneedleless connector) without the reversed internal blunt cannulacontacting the inner surface of the tip. In some embodiments, such anglewill be 5 degrees, or 7 degrees, or 10 degrees, or 12.5 degrees, or 15degrees, or 20 degrees, or even higher. While not limiting to theinventive subject matter, contemplated syringes may have a fixed or arotating (typically polymeric) lock portion. Still further, it iscontemplated that contemplated syringes will have a tip cap rubbersurface contact area of equal or more than 2.4 mm², and more preferablyequal or more than 4.8 mm². In still further contemplated embodiments,the syringe has a glide force of about 1 to about 30 N, about 1 to about20N, or about 1 to about 10N. In other embodiments, the syringe has abreak loose force of about 10 to about 30 N or about 15 to 25N.Exemplary syringes are commercially available, for example, from BectonDickinson under the brand name Hylok or LLEC (Luer Lock extendedchannel), which are commonly used for viscous materials such as dermalfillers.

It should be recognized that the syringes contemplated herein will beparticularly suitable for use with drug compositions that areadministered in an emergency setting where administration must beperformed promptly and without interruption necessitated by clearing aclogged line, reconnecting a malfunctioning syringe, and/or preparing anew vascular access. Typical drugs for use with the syringes presentedherein include those used in cardiac/vascular emergencies, pulmonaryemergencies, anaphylaxis, etc. Consequently, suitable drugs includesuccinylcholine, ephedrine, amiodarone, adenosine, epinephrine,atropine, methylprednisolone, metoprolol, diltiazem, and procainamide.In most embodiments, the syringes will be prefilled with a volume of thedrug, typically at a volume of at least 1 mL, or at least 5 mL, or atleast 10 mL, or about 5 mL or about 10 mL. As will be readilyappreciated, the emergency drug in such products will be present at apharmaceutically effective concentration to treat any emergencycondition. Suitable formulation types of the drug compositions includesolutions with single, binary, or higher solvent systems, dispersedsystems (e.g., preferably emulsions or suspensions)

Of course, it should also be appreciated that the prefilled syringe maybe provided with an IV administration set or other bags or tubing thatwill most typically comprise at least one needleless connector that mayor may not have a reversed internal blunt cannula. Still further, itshould be noted that the prefilled syringe will typically be sterilizedusing terminal sterilization, e-beam or gamma ray radiation, ethyleneoxide, etc.

Moreover, it should be recognized that contemplated prefilled glasssyringes are especially advantageous for drug compositions that aresensitive to components that would otherwise leach from a plasticsyringe (such as plasticizers, dyes, metals, etc.), particularly wherethe pH of the drug composition is in the acidic range (e.g., equal orless than 5.0, or equal or less than 4.5, or equal or less than 4.0, orequal or less than 3.5), where the drug is sensitive to oxygen ingress,or where the composition comprises a solvent that is incompatible withpolymers used in plastic syringes such as polypropylene or polyethylene.Therefore, and viewed form a different perspective, contemplated systemsand methods will also advantageously help improve chemical stability ofotherwise relatively labile compounds (e.g., succinylcholine) underrefrigeration conditions (about 2° C. to about 8° C., or about 5° C.)and at room temperature (about 25° C.).

For example, the stability of a succinylcholine composition in a glasssyringe will typically be increased such that total impurities are equalor less than 12%, or equal or less than 10%, more typically equal orless than 8%, even more typically equal or less than 6%, or equal orless than 4%, or equal or less than 2% after storage at 2-8° C. for 12,15, 18, or 24 months as determined HPLC as is described in more detailbelow. Thus, total impurities will preferably be in the range of between1-3%, or between 2-5%, or between 4-8%, or between 5-10% after storageat 2-8° C. for 15 months as determined HPLC. Additionally, it iscontemplated that after storage of a succinylcholine composition in aglass syringe at 2-8° C. for 12, 15, 18, or 24 months, no more than 8%,or no more than 6%, or no more than 4%, or no more than 2% ofsuccinylmonocholine chloride (as primary degradation product) arepresent. Thus, succinylmonocholine chloride may be present after storageof a succinylcholine composition in a glass syringe at 2-8° C. for 12,15, 18, or 24 months in a range of between 1-3%, or between 2-5%, orbetween 4-8%, or between 5-10%.

In further contemplated aspects, improved stability is also contemplatedwhere the succinylcholine composition is stored in a glass syringe atabout 25° C. For example, succinylmonocholine chloride may be presentafter storage of a succinylcholine composition in a glass syringe atabout 25° C. for 14-60 days (or for 7-14 days, or for 14-21 days, or for21-28 days, or for 28-40 days, or for 40-60 days) in a range of between1-3%, or between 2-5%, or between 4-8%, or between 5-10%, particularlywhere the prefilled syringe was not previously subjected extendedstorage at 2-8° C. In such cases, for example where the previousrefrigerated storage was between 1-3 months, the succinylmonocholinechloride may be present after subsequent storage about 25° C. for 14-60days (or for 7-14 days, or for 14-21 days, or for 21-28 days, or for28-40 days, or for 40-60 days) in a range of between 2-5%, or between4-8%, or between 5-10%. Likewise, where the previous refrigeratedstorage was between 3-6 months, the succinylmonocholine chloride may bepresent after subsequent storage about 25° C. for 14-50 days (or for7-14 days, or for 14-21 days, or for 21-28 days, or for 28-40 days, orfor 40-50 days) in a range of between 3-6%, or between 5-9%, or between8-12%, and where the previous refrigerated storage was between 6-15months, the succinylmonocholine chloride may be present after subsequentstorage about 25° C. for 14-40 days (or for 7-14 days, or for 14-21days, or for 21-28 days, or for 28-40 days) in a range of between 3-7%,or between 5-10%, or between 8-12%.

In some embodiments, the drug composition comprises a drug for emergencymedical administration, a tonicity agent, optionally one or more pHadjusting agents, and water.

In some embodiments, the drug for emergency medical administration issuccinylcholine, selected from the group consisting of ephedrine,amiodarone, adenosine, epinephrine, atropine, methylprednisolone,metoprolol, diltiazem, and procainamide, and pharmaceutically acceptablesalts thereof. In preferred embodiments, the drug for emergency medicaladministration is succinylcholine or a pharmaceutically acceptable saltthereof, and most preferably, succinylcholine chloride. In someembodiments, the drug for emergency medical administration is present inthe composition in a therapeutically effective amount. In someembodiments, the drug for emergency medical administration issuccinylcholine chloride and the succinylcholine chloride is present inthe composition in an amount of about 10 to about 30 mg/mL, about 15 toabout 25 mg/mL, or about 20 mg/mL.

In some embodiments, the tonicity agent is selected from the groupconsisting of dextrose, mannitol, potassium chloride, and sodiumchloride. In preferred embodiments, the tonicity agent is sodiumchloride. In some embodiments, the tonicity agent is present in thecomposition in an amount sufficient to provide an isotonic solution. Insome embodiments, the tonicity agent is present in the composition in anamount sufficient to provide an osmolality of about 260 to about 340mOsm/kg. In some embodiments, the tonicity agent is sodium chloride andthe sodium chloride is present in the composition in an amount of about4 to about 7 mg/mL, about 5 to about 6 mg/mL, about 5 mg/mL, or about 6mg/mL.

In some embodiments, the pH adjusting agents are selected from the groupconsisting of acidifying agents, alkalizing agents, and bufferingagents. In some embodiments, the pH adjusting agent is selected from thegroup consisting of citric acid, acetic acid, hydrochloric acid, sodiumhydroxide, sodium citrate, potassium hydroxide, and potassium citrate.In preferred embodiments, pH adjusting agent is hydrochloric acid and/orsodium hydroxide. In some embodiments, the pH adjusting agent is presentin the composition in an amount sufficient to provide a pH of about 3 toabout 4.5, about 3 to about 4, about 3.5 to about 4.5, or about 3.5 toabout 4, or about 3.6.

EXAMPLES Example 1: Succinylcholine Composition

In one example, where the drug composition comprises succinylcholine, a5 mL or 10 mL glass syringe (e.g., syringes with inner tip diameter of1.7 mm) can be filled with a composition as shown in Table 1 where thecomposition has a pH of about 3.0 to about 4.5. Tonicity is adjusted toabout 260 to about 340 mOsm/kg, and in preferred aspects, thesuccinylcholine chloride is present in the succinylcholine compositionin an amount of about 20 mg/mL and the sodium chloride is present in thesuccinylcholine composition in an amount of about 5.50-6.00 mg/mL.

TABLE 1 Ingredient Grade Function Qty/mL Succinylcholine Chloride USPActive ingredient 20.0 mg Sodium Chloride USP Tonicity agent 5.56 mgHydrochloric Acid NF pH adjuster q.s. for pH adjustment to about pH 3.6Sodium Hydroxide NF pH adjuster q.s. for pH adjustment to about pH 3.6Water for Injection USP Vehicle q.s. to 1.0 mL 5 ml per Syringe 10 mlper Syringe

Example 2: Stability of a Succinylcholine Composition at 25° C.

Advantageously, thusly prefilled glass syringes afford relatively highstability and purity throughout extended periods of storage despite theacidic pH of the solution.

Three batches of the succinylcholine composition of Example 1 in a 5 mLBecton Dickinson LLEC glass syringe with inner tip diameter of 1.7 mmwere prepared and stability was tested over 3 months of storage at 25°C. and 60% relative humidity. Content of succinylcholine chloride,impurities succinylmonocholine chloride, succinic acid, unidentifiedimpurity 1, unidentified impurity 2, and total impurities were measuredat 0, 1, 2, and 3 months by HPLC according to Example 4 below.Unidentified impurity 1 and unidentified impurity 2 are referenced inthe USP monograph for impurity detection in succinylcholine, FirstSupplement to USP 39-NF 34. Appearance, pH, osmolality, and particulatecontent were also measured at 0, 1, 2, and 3 months. The results areincluded in Table 2 below.

TABLE 2 Impurity Impurity Total P ≥ 10 P ≥ 25 Osmolality Month BatchAppearance* pH SCC SMCC SA 1 2 impurities μm μm (mOsm/kg) 0 1 complies3.9 99.3% 0.5% <LOQ <LOQ <LOQ 0.5% 34 0 314 0 2 complies 3.9 99.8% 0.4%ND 0.2% <LOQ 0.4% 25 0 313 0 3 complies 3.9 97.6% 0.4% ND <LOQ 0.2% 0.4%65 1 312 1 1 complies 3.4 93.5% 2.5% 0.1% 0.2% ND 2.7% — — — 1 2complies 3.4 94.8% 2.3% 0.1% <LOQ 0.1% 2.4% — — — 1 3 complies 3.4 94.5%2.2% 0.1% <LOQ <LOQ 2.3% — — — 2 1 complies 3.3 93.8% 4.0% 0.3% 0.5%0.1% 4.3% — — — 2 2 complies 3.3 93.8% 3.9% 0.3% 0.3% 0.3% 4.2% — — — 23 complies 3.3 93.8% 3.8% 0.2% 0.3% 0.3% 4.0% — — — 3 1 complies 3.391.6% 4.9% 0.4% 0.2% <LOQ 5.4% 75 1 316 3 2 complies 3.3 92.7% 4.9% 0.4%0.1% <LOQ 5.3% 63 0 318 3 3 complies 3.3 92.6% 4.8% 0.4% 0.1% <LOQ 5.2%133  0 316 ND = not detected; *Clear, colorless solution essentiallyfree of visible particles; SCC: Succinylcholine chloride; SMCC:Succinylmonocholine chloride; SA: Succinic acid: P: Particle; <LOQ =that the amount detected is less than the limit of quantitation of theHPLC method. — = not measured.

As illustrated by Table 2 above, the succinylcholine composition in theglass syringe contained not more than about 6% total impurities afterstorage at 25° C. for 3 months as determined by HPLC. Likewise, withrespect to degradation it was determined that the succinylcholinecomposition in the glass syringe contained not more than about 4%succinylmonocholine chloride (as primary degradation product) afterstorage at 25° C. for 3 months as determined by HPLC, and that thesuccinylcholine composition in the glass syringe contained not more thanabout 1% succinic acid after storage at 25° C. for 3 months asdetermined by HPLC.

Example 3: Stability of a Succinylcholine Composition at 5° C.

Stability of the three batches of Example 2 was also tested over 3months of storage at 5° C. Content of succinylcholine chloride,impurities succinylmonocholine chloride, succinic acid, unidentifiedimpurity 1, unidentified impurity 2, and total impurities were measuredat 0 and 3 months by HPLC according to Example 4 below. Unidentifiedimpurity 1 and unidentified impurity 2 are referenced in the USPmonograph for impurity detection in succinylcholine, First Supplement toUSP 39-NF 34. Appearance, pH, osmolality, and particulate content werealso measured at 0 and 3 months. The results are included in Table 3below.

TABLE 3 Impurity Impurity Total P ≥ 10 P ≥ 25 Osmolality Month BatchAppearance* pH SCC SMCC SA 1 2 impurities μm μm (mOsm/kg) 0 1 complies3.9 99.3% 0.5% <LOQ <LOQ <LOQ 0.5% 34 0 314 0 2 complies 3.9 99.8% 0.4%ND 0.2% <LOQ 0.4% 25 0 313 0 3 complies 3.9 97.6% 0.4% ND <LOQ 0.2% 0.4%65 1 312 3 1 complies 3.7 98.3% 1.1% <LOQ 0.2% <LOQ 1.1% 66 0 310 3 2complies 3.6 98.9% 0.9% <LOQ 0.1% <LOQ 0.9% 88 1 311 3 3 complies 3.799.3% 0.9% <LOQ 0.1% <LOQ 0.9% 63 0 310 ND = not detected; *Clear,colorless solution essentially free of visible particles; SCC:Succinylcholine chloride; SMCC: Succinylmonocholine chloride; SA:Succinic acid: P: Particle; <LOQ = that the amount detected is less thanthe limit of quantitation of the HPLC method. — = not measured.

As illustrated by Table 3 above, the succinylcholine composition in theglass syringe contained not more than about 2% total impurities afterstorage at 5° C. for 3 months as determined by HPLC. Likewise, withrespect to degradation it was determined that the succinylcholinecomposition in the glass syringe contained not more than about 2%succinylmonocholine chloride (as primary degradation product) afterstorage at 5° C. for 3 months as determined by HPLC, and that thesuccinylcholine composition in the glass syringe contained not more thanabout 1% succinic acid after storage at 5° C. for 3 months as determinedby HPLC.

Example 4: Analytic Protocols

In general, analytic protocols for succinylcholine are well known in theart, and the following TLC and HPLC protocols are suitable for useherein (which are based on the USP monographs):

Analytic Protocol (TLC):

Standard solution: 1 mg/mL of USP Succinylcholine Chloride RS in water;Sample solution: 1 mg/mL of succinylcholine chloride in water;Adsorbent: 0.25-mm layer of chromatographic silica gel with anapplication volume of 1 mcL. The plate is run with a developing solventsystem that consists of acetone and 1 N hydrochloric acid (1:1).Analysis is performed by running standard and sample solution inparallel. Sample and standard spots are detected by heating the plate to105° C. for 5 min, followed by cooling and spraying with potassiumbismuth iodide test solution and subsequent heating to 105° C. foranother 5 min.

Analytic Protocol (HPLC) for succinylcholine:

Mobile phase: Prepare a 1 in 10 solution of 1 N aqueoustetramethylammonium chloride in methanol. Adjust with hydrochloric acidto a pH of about 3.0.

Standard solution: 8.8 mg/mL of USP Succinylcholine. SuccinylcholineChloride Chloride RS prepared as follows. Transfer a suitable amount ofUSP Succinylcholine Chloride RS to a suitable volumetric flask anddissolve in 40% of the total volume of water. Dilute with Mobile phaseto volume while mixing.

Sample solution: 8.8 mg/mL of Succinylcholine Chloride prepared asfollows. Transfer a suitable amount of Succinylcholine Chloride to asuitable volumetric flask and dissolve in 40% of the total volume ofwater. Dilute with Mobile phase to volume while mixing.

Conventional HPLC system is operated using UV detection at 214 nm and a4-mm×25-cm, 10 μm L3 packing (normal phase, silica) at a flow rate of0.75 ml/min.

Analysis is performed on standard and sample solutions and percentage ofsuccinylcholine chloride is calculated using the following equation:Result=(r_(U)/r_(S))×(C_(S)/C_(U))×100, where r_(U) is peak responsefrom the sample solution, r_(S) is peak response from the standardsolution, C_(S) is concentration of USP Succinylcholine Chloride RS inthe standard solution (mg/mL), and C_(U) is concentration ofSuccinylcholine Chloride in the sample solution (mg/mL).

Analytic Protocol (HPLC) for impurities:

Buffer: 3.85 g/L of anhydrous sodium 1-pentanesulfonate, 2.9 g/L ofsodium chloride, and 1% (v/v) of 1 N sulfuric acid in water.

Mobile phase: Acetonitrile and Buffer (5:95).

Standard solution: 0.05 mg/mL of USP Succinylmonocholine Chloride RS inMobile phase.

Sample solution: Sample solution: 10 mg/mL of Succinylcholine Chloridein mobile phase.

Conventional HPLC system is operated using UV detection at 214 nm and a4.6-mm×25-cm, L1 packing (octadecyl silane chemically bonded to poroussilica or ceramic micro-particles, 1.5 to 10 μm in diameter) at a flowrate of 0.75 ml/min.

Analysis is performed on standard and sample solutions and percentage ofsuccinylcholine chloride is calculated using the following equation:Result=(r_(U)/r_(S))×(C_(S)/C_(U))×(1/F)×100, where r_(U) is peakresponse from the sample solution, r_(S) is peak response from thestandard solution, C_(S) is concentration of USP SuccinylcholineChloride RS in the standard solution (mg/mL), C_(U) is concentration ofSuccinylcholine Chloride in the sample solution (mg/mL), and F is therelative response factor.

Example 5: Syringe Parameters

Break loose force and glide force were also measured in quintuplicate ateach time point in Examples 2 and 3 above. The results are included inTable 4 below:

TABLE 4 Break Loose Force Glide Force Month Temperature Batch (Newtons)(Newtons) 0 25° C. 1 16, 16, 16, 16, 13 6, 24, 6, 20, 5 0 25° C. 2 13,16, 14, 18, 15 5, 11, 6, 7, 11 0 25° C. 3 16, 14, 18, 18, 24 14, 13, 9,6, 7 1 25° C. 1 16, 19, 21, 18, 16 6, 6, 21, 17, 12 1 25° C. 2 19, 17,13, 16, 17 28, 6, 8, 9, 6 1 25° C. 3 18, 21, 15, 15, 21 8, 23, 16, 12, 72 25° C. 1 20, 18, 19, 17, 22 5, 6, 7, 4, 6 2 25° C. 2 23, 19, 16, 19,17 5, 10, 6, 5, 6 2 25° C. 3 16, 18, 16, 21, 21 9, 6, 8, 11, 10 3 25° C.1 22, 19, 19, 19, 18 9, 12, 8, 8, 6, 9 3 25° C. 2 15, 19, 18, 22, 19 6,7, 16, 13, 8 3 25° C. 3 25, 25, 22, 14, 17 6, 9, 6, 6, 6 3  5° C. 1 23,16, 19, 20, 18 23, 7, 6, 33, 7 3  5° C. 2 20, 17, 20, 22, 10 9, 6, 18,7, 6 3  5° C. 3 15, 17, 18, 16, 20 9, 26, 6, 7, 8

As used herein, the term “administering” a pharmaceutical composition ordrug refers to both direct and indirect administration of thepharmaceutical composition or drug, wherein direct administration of thepharmaceutical composition or drug is typically performed by a healthcare professional (e.g., physician, nurse, etc.), and wherein indirectadministration includes a step of providing or making available thepharmaceutical composition or drug to the health care professional fordirect administration (e.g., via injection, infusion, oral delivery,topical delivery, etc.).

In some embodiments, the drug composition in the prefilled syringe isadministered to a patient via the patient's intravenous line. In someembodiments, the drug composition in the prefilled syringe isadministered to the patient by reversibly attaching the syringe to thepatient's intravenous line via the Luer-lock, delivering the drugcomposition from the syringe into the patient's intravenous line, andadministering the drug composition from the patient's intravenous lineto the patient. The succinylcholine drug composition is typicallyadministered to the patient at a rate sufficient to cause the desiredskeletal muscle relaxation. In some embodiments, the succinylcholinedrug composition is administered to the patient at a rate of about 0.5to about 10 mg per minute or about 2 to about 5 mg per minute, or about2.5 to about 4.3 mg per minute. In some embodiments, the succinylcholinedrug composition is administered to the patient in an amount of about0.01 to about 3 mg/kg, about 0.04 to about 0.07 mg/kg, about 0.3 toabout 1.1 mg/kg, about 0.6 mg/kg, 1 mg/kg, or 2 mg/kg.

In some embodiments, the present invention encompasses a method forproviding skeletal relaxation comprising administering thesuccinylcholine drug composition in a prefilled syringe to a patient inneed thereof via the patient's intravenous line. In some embodiments,the succinylcholine drug composition is administered as an adjunct togeneral anesthesia, to facilitate tracheal intubation, or to provideskeletal muscle relaxation during surgery or mechanical ventilation.

The recitation of ranges of values herein is merely intended to serve asa shorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided with respectto certain embodiments herein is intended merely to better illuminatethe full scope of the present disclosure, and does not pose a limitationon the scope of the invention otherwise claimed. The term “about” whereused in conjunction of a numeric value refers to a range of +/−10% ofthat numeric value, inclusive. No language in the specification shouldbe construed as indicating any non-claimed element essential to thepractice of the claimed invention.

It should be apparent to those skilled in the art that many moremodifications besides those already described are possible withoutdeparting from the full scope of the concepts disclosed herein. Thedisclosed subject matter, therefore, is not to be restricted except inthe scope of the appended claims. Moreover, in interpreting both thespecification and the claims, all terms should be interpreted in thebroadest possible manner consistent with the context. In particular, theterms “comprises” and “comprising” should be interpreted as referring toelements, components, or steps in a non-exclusive manner, indicatingthat the referenced elements, components, or steps may be present, orutilized, or combined with other elements, components, or steps that arenot expressly referenced. Where the specification claims refers to atleast one of something selected from the group consisting of A, B, C . .. and N, the text should be interpreted as requiring only one elementfrom the group, not A plus N, or B plus N, etc.

What is claimed is:
 1. A method for intravenously administeringsuccinylcholine to a patient in need thereof, comprising: (a) providinga prefilled glass syringe containing a succinylcholine composition,wherein the succinylcholine composition has a pH of about 3.0 to about4.5, wherein the succinylcholine composition disposed in the glasssyringe contains not more than about 6% total impurities after storageat 2-8° C. for 12 months, followed by storage at about 25° C. for 14days as determined by HPLC, and wherein the syringe has a Luer-lock anda syringe tip with an internal channel that has a diameter of about 1.7mm; (b) reversibly attaching the syringe to a patient's intravenous linevia the Luer-lock; (c) delivering the succinylcholine composition fromthe syringe into the patient's intravenous line; and (d) administeringthe succinylcholine composition from the patient's intravenous line tothe patient.
 2. The method of claim 1, wherein the step of reversiblyattaching the syringe to a patient's intravenous line comprisesattaching the syringe to a needleless connector.
 3. The method of claim2 wherein the needleless connector has a reversed internal bluntcannula.
 4. The method of claim 1, wherein the glass syringe has avolume of at least 5 mL.
 5. The method of claim 1, wherein thesuccinylcholine composition has an osmolality of about 260 to about 340mOsm/kg.
 6. The method of claim 1, wherein the succinylcholine chlorideis present in the succinylcholine composition in an amount of about 20mg/mL and sodium chloride is present in the succinylcholine compositionin an amount of about 6 mg/mL.
 7. The method of claim 1, wherein thesuccinylcholine composition further comprises a pH adjusting agent. 8.The method of claim 7, wherein the pH adjusting agent is hydrochlorideacid and/or sodium hydroxide.
 9. The method of claim 1, wherein the pHof the succinylcholine composition is about 3.6.
 10. The method of claim1, wherein the syringe has a glide force of about 1 to about 20 N. 11.The method of claim 1, wherein the syringe has a break loose force ofabout 10 to about 30 N.
 12. The method of claim 1, wherein thesuccinylcholine composition is administered to the patient at a rate ofabout 0.5 to about 10 mg per minute.
 13. The method of claim 1, whereinthe syringe contains about 5 mL of the succinylcholine composition, orwherein the syringe contains about 10 mL of the succinylcholinecomposition.
 14. The method of claim 1, wherein the succinylcholinecomposition comprises succinylcholine chloride, sodium chloride, andwater, wherein the succinylcholine composition is substantially free ofpreservatives.
 15. The method of claim 1, wherein the succinylcholinecomposition disposed in the glass syringe contains not more than about6% total impurities and no more than 4% succinylmonocholine chlorideafter storage at 2-8° C. for 12 months, followed by storage at about 25°C. for 14 days, as determined by HPLC.
 16. The method of claim 1,wherein the succinylcholine composition disposed in the glass syringecontains not more than about 4% total impurities not more than about 4%succinylmonocholine chloride after storage at 2-8° C. for 12 months,followed by storage at about 25° C. for 14 days, as determined by HPLC.17. The method of claim 1, wherein the succinylcholine compositiondisposed in the glass syringe contains not more than about 1% succinicacid after storage at 2-8° C. for 12 months, followed by storage atabout 25° C. for 14 days, as determined by HPLC.
 18. A method forproviding skeletal muscle relaxation to a patient in need thereof,comprising: a) providing a prefilled glass syringe containing asuccinylcholine composition, wherein the succinylcholine composition hasa pH of about 3.0 to about 4.5, wherein the succinylcholine compositiondisposed in the glass syringe contains not more than about 6% totalimpurities after storage at 2-8° C. for 12 months, followed by storageat about 25° C. for 14 days, as determined by HPLC, and wherein thesyringe has a Luer-lock and a syringe tip with an internal channel thathas a diameter of about 1.7 mm; b) reversibly attaching the syringe to apatient's intravenous line via the Luer-lock; c) delivering thesuccinylcholine composition from the syringe into the patient'sintravenous line; and d) administering the succinylcholine compositionfrom the patient's intravenous line to the patient.
 19. The method ofclaim 18, wherein the step of reversibly attaching the syringe to apatient's intravenous line comprises attaching the syringe to aneedleless connector that has a reversed internal blunt cannula, andoptionally wherein the succinylcholine composition comprisessuccinylcholine chloride, sodium chloride, and water, wherein thesuccinylcholine composition is substantially free of preservatives.